CN1013866B - Process for preparation of highly pure acarbose - Google Patents
Process for preparation of highly pure acarboseInfo
- Publication number
- CN1013866B CN1013866B CN86108259A CN86108259A CN1013866B CN 1013866 B CN1013866 B CN 1013866B CN 86108259 A CN86108259 A CN 86108259A CN 86108259 A CN86108259 A CN 86108259A CN 1013866 B CN1013866 B CN 1013866B
- Authority
- CN
- China
- Prior art keywords
- acarbose
- chromatographic column
- solution
- volume
- wash
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/08—Deoxysugars; Unsaturated sugars; Osones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Quinoline Compounds (AREA)
- Treatment Of Sludge (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Electrotherapy Devices (AREA)
Abstract
A purified acarbose which contains less than 10% by weight of sugar-like secondary components is obtained by column chromatograph of a solution of prepurified acarbose with a pH 4 to 7. The column contains as a packing material a weakly acid cation exchanger which has carboxyl groups and is based on dextran, agarose and cellulose or exchangers which are derived from the latter with the addition of polyamide.
Description
The present invention relates to highly purified acarbose (acarbose) and preparation method thereof, also relate to high-purity acarbose as the application of medicine and the preparation of this medicine.
Acarbose can be used as the inhibitor of human small intestine's sucrase mixture, and acarbose is as the medicine of treatment diabetes.
Acarbose (Acarbose) is 0-4,6-two deoxidation-4-((IS, 4R, 5S, 6S)-4,5,6-trihydroxy--3-(methylol)-2-tetrahydrobenzene-1-amino)-α-D-glucopyranosyl-(1 → 4)-O-α-D-glucopyranosyl-(1 → 4)-D-pyranoglucose.
Inhibitor can be by fermentation obtains (seeing German patent specification 2,209,832, German patent specification 2 to actinoplanes kind (Actinoplanes species), 209,834, German patent specification 2,064,092), and must separate from sending out gravy pure.For this reason, the introduction of existing these methods of purification.(see German patent specification 2,347,782 and No. 2,719,912, German patent specification).
In these methods of purification, acarbose is bonded in the strong-acid cation exchanger, and with salts solution or mainly with diluted acid to its wash-out.With in the anionite and after the acarbose that obtains, its content is the 78-88%(high pressure lipuid chromatography (HPLC) in dry substance).These Separation Products still contain impurity, and what promptly contain the 10-15% that has an appointment has the submember of color reaction, ash content and the some colored components of 1-4% to sugar.The acarbose that is used for human body medicine, need have higher purity, yet, according to above-mentioned prior art, only by replacing the strong-acid cation exchanger with the Weak-acid cation exchanger, be to meet the requirements of because the Weak-acid cation exchanger can not be fully in conjunction with the acarbose of very weak alkalescence, and impurity appears in eluate.
Now, make us having found unexpectedly, in the pH value scope of strictness control,, can purify out from remaining salt, coloring matter and sacchariferous alkaline submember by the pre-acarbose of purifying of prior art by a one-step process with very weak acid hydrophilic cations exchanger.The content of the acarbose after purifying like this is increased to and is at least 90%(by weight), better, reach 95-98%(by weight) or higher; Sulfated ash is reduced to 0-0.5%; The carbohydrate submember is reduced to and is less than 10%(by weight), be more preferably, be reduced to 2-5%(by weight) or lower.
Therefore, the present invention relates to its carbohydrate submember content and be less than 10%(weight meter) acarbose.
Be 2-5%(weight to contain the carbohydrate submember among the present invention) acarbose be preferable.And best be acarbose contain be lower than 2%(by weight) the carbohydrate submember.
In order to prepare acarbose of the present invention, adopted special chromatography, used the solution of making through pre-acarbose of purifying.For example this solution can be by German patent specification 2,719, the method for being introduced for No. 912 and making.With concentration is that 1-20%, pH are that 3.5-6.5(is preferably 4.0-5.5) above-mentioned solution be added in the chromatographic column.Suitable column filling is the Weak-acid cation exchanger, it has carboxyl functional group, and be matrix with dextran, agarose and Mierocrystalline cellulose, or the exchanger of being derived and obtaining by the said components that has added polyacrylamide, for example commercially available all types of ion-exchangers have: weak-type cationite (CM-Sephadex
), substituting group sepharose (CM-Sepharose
), carboxymethyl cellulose (CM-Cellulose
) and CM-Cellufine
Especially it should be noted that to contain carboxyl functional group, and be that the commodity of matrix can not be used to this purification with the weak-type exchanger with polystyrene, polyacrylic acid or polymethyl acrylic acid.
The invention further relates to preparation contains less important composition of carbohydrate and is less than 10%(by weight) the method for acarbose, it is characterized in that with pH be 4 to 7, concentration is 1-20%(weight meter) the acarbose aqueous solution of pre-purification be added in the chromatographic column, this post contains the Weak-acid cation exchanger as packing material, exchanger has carboxyl functional group, and with dextran, agarose and Mierocrystalline cellulose are matrix; Or by the above-mentioned substance that has added polymeric amide the resulting exchanger of deriving.Distilled water with the degassing carries out wash-out to chromatographic column specially, and in suitable position, available habitual mode is separated acarbose from the post elutriant.
The pre-purification acarbose aqueous solution volume that joins in the post is restricted.The maximum volume of the aqueous solution that can add is equivalent to the packing volume of post, preferably is less than 60% of column volume.For this reason, be a certain amount of acarbose of purifying, the concentration of aqueous solution that is adopted can not be too low, because the ion-exchanger of the usefulness that is suitable for most purifying is easy to shrink, concentration should be controlled at scope on the upper side.Its concentration with 7-20% for well.
After adding the aqueous solution, carry out wash-out with degassing distilled water coupled columns specially.In this process, at first flow out salt, neutral sugar and coloured concomitants, then, more lentamente, the acarbose that is the crest of a broad flows out.Carbohydrate alkalescence submember is stayed on the post, just is removed up to column regeneration the time.Like this, acarbose is present in the highly purified aqueous solution that pH is 6-7, can it be concentrated with habitual mode, and be dried with highly purified state.
Acarbose performance on the chromatographic column depends on a number of factors.In actual mechanical process, a crucial factor is the equilibration pH value of column filling and the temperature in the chromatographic run process.
The variation of column filling pH value can change the elution property of capacity and acarbose.In pH neutral, it is inadequate that the deceleration of acarbose is compared with salt, thereby separation is incomplete.And when the about 3.5-4 of acid ph value, the deceleration of acarbose is very big, and water can not come out its wash-out fully.In actual mechanical process, with regard to each exchanger, the pH value an of the best need be arranged all.It is comparatively suitable when in general, the pH value is between 4.3 and 5.0.When loading level was high, best pH value was about 4.6, when loading level hangs down, and best pH value about 4.9.At this moment yield is all maximum.
Second important factor is temperature.Temperature is lower, and ion-exchanger is just stronger to the absorption of acarbose, and the capacity of post is bigger, and the wash-out of acarbose is just slower.This just means and has obtained an asymmetric peak that the volume of acarbose fraction is very big.Therefore, in room temperature or when being lower than room temperature, material being added, and after salt and colored component wash-out, post is added to 25-90 ℃, be preferably 40-70 ℃, is more favourable.Like this, also caused the rapid wash-out of acarbose, and its yield is also high.
Come regenerating ion-exchanger with damping fluid, for example usable concentration is 0.1 to 0.5M, pH is at the sodium acetate buffer of the required scope of equilibration.After this, the de aerated water washing chromatographic column with pure is reduced to 0.1 milli Siemens/cm (mS/cm) (during room temperature) up to electric conductivity.
When diagram is described separating process, with the time hour fixing on the X-coordinate, and corresponding to the specific refractory power and the different electric rate (dotted line is represented) of elutriant.In addition, indicated the temperature mark.
Measure the content of acarbose in the final product (with regard to anhydrous substances) specially with liquid phase chromatography (high pressure lipuid chromatography (HPLC)).Measuring method is as follows:
The high pressure liquid chromatograph of band thermocolumn process furnace,
Stainless steel metal post, length are 25 centimetres, and internal diameter is 4 millimeters,
Filling amino phase, 5 μ m (multi-hole type silica gel NH for example
2,
(Lichrosorb NH
2), E.Merck, or full multi-hole type silica gel
Silanization bonded stationary phase (strong polarity, aminopropyl)
（Hypersil APS），Shandon〕。
Reagent 1. acetonitriles (for example, LiChrosolv, E.Merck),
2. potassium primary phosphate, analytical pure,
3. two hypophosphite monohydrate disodium hydrogens, analytical pure
Testing liquid with 200 milligrams of substance dissolves of accurate weighing in a scale capacity
Bottle adds water to 10.0ml.Concentration is 20 mg/ml.
Comparison solution is dissolved in the specified standards volume with the reference material of an ampoule content
Water in.
Elutriant acetonitrile/phosphate buffered saline buffer (71+29, volume), phosphoric acid salt is slow
Towards liquid:, and add water to 1000 milliliters with 600 milligrams of potassium primary phosphates and 350 milligram of two hypophosphite monohydrate disodium hydrogen dissolving.With the solution warp
0.8 μ m, model is that AAWP Millipore strainer leaches.
Flow velocity 2.2 ml/min
35 ℃ of post furnace temperatures
Detect ultraviolet ray, 210 millimicrons
Injection rate 10 microlitres contain 0.2 milligram in per 10 microlitres
The about 0.25 AUFS(aufs of the full-scale deflection of register)
The calculating of acarbose content
G= (P
P×C×100,000)/(P
V×W
P×(100-b))
The percentage composition of G=acarbose is that benchmark calculates with the anhydrous substances
P
PThe acarbose peak area of=testing liquid
P
VThe acarbose peak area (making standard) of=comparison solution
W
P=in the weight of milligram sample
Every milliliter of comparison solution concentration of C=in the milligram acarbose
Percent moisture in the b=sample.
Suppress the inhibition activity that assay method is measured acarbose with sucrase, and suppress unit (SIU) with sucrase inhibition assay method and sucrase it has been made record.The said determination method be by people such as L.M ü ller, B.Junge at " enzyme inhibitors " (" Enzyme Inhibitors "), U.Brodbeck ed., Verlag Chemie, 1980 years, 109 pages) in introduce.
The present invention includes pharmaceutical preparation, the vehicle that said preparation is suitable for, also contain active compound of the present invention on the medicine that contains nontoxic and inert; Or said medicine preparation list is made up of active compound of the present invention; The present invention also comprises the method for preparing this class preparation.
The present invention also comprises with various dosage being the pharmaceutical preparation of unit.This means that preparation is various form, as tablet, dragee, capsule, pill, suppository and ampoule, wherein content of active substance is equivalent to a part or the multiple of dose.For example: dose unit can be 1,2,3,4 times of dose, or 1/2,1/3 or 1/4.The contained active compound amount of dose preferably dosing time given amount, be equivalent to usually day clothes dosage whole, half or 1/3rd or 1/4th.
The vehicle that is suitable on nontoxic, the inert medicine can be understood that various solid-state, semi-solid or liquid thinners, filling agent and formulation adjuvant.
Tablet, drageeing, capsule, pill, granula, suppository, solution, suspension and emulsion, paste, ointment (agent), gel, emulsifiable paste, lotion, pulvis and sprays can be listed as preferable pharmaceutical preparation.
Tablet, drageeing, capsule, pill, granula can contain active compound or contain and vehicle commonly used and the active compound of depositing, vehicle for example can be, (a) filling agent and swelling agent, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicon-dioxide, (b) tackiness agent, as carboxymethyl cellulose, alginate, gelatin and Polyvinylpyrolidone (PVP), (c) wetting agent, as glycerine, (d) disintegrating agent is as agar, lime carbonate and sodium bicarbonate, (e) solution retarding agent, as paraffin, (f) absorb accelerator, as quaternary ammonium compound; (g) treating compound, as hexadecanol or glycerol monosterate, (h) sorbent material, as kaolin and wilkinite, (i) lubricant is as talcum, calcium stearate and Magnesium Stearate and solid-state polyoxyethylene glycol; Or contain and list in (a) mixture to (i) material.
Tablet, drageeing, capsule, pill and granula can have covering commonly used and shell, and at random contain opacifying agent; Also can have such composition: make its only release of active ingredients, or preferably at random discharge active ingredient with slow form in certain part of enteron aisle.Polymkeric substance and wax can be used as the example of employed embedding (implantation) component.
In addition, active compound or at random also can be particulate encapsulate shape with above-mentioned one or more vehicle and the active compound deposited.
Suppository also contains habitual water-soluble or water-insoluble vehicle except containing active compound, as: polyoxyethylene glycol, fat (as theobroma oil) and higher ester fat are (as band C
16Lipid acid and C
14Alcohol), or the mixture of these materials.
Ointment, paste, emulsifiable paste, gel also can contain various habitual vehicle except containing active compound, Oil of Eucalyptus and sweetener (as asccharin).
The active compound of treatment usefulness should be present in the above-mentioned pharmaceutical preparation with its total mixture weight percent concentration 0.1 to 99.5%, preferably 0.5 to 95%.
Can be by known method, by mode commonly used,, or active compound and one or more vehicle are mixed mutually make the said medicine preparation for example by with a kind of active compound.
The present invention also comprises by the prepared active compound of the present invention with contain the purposes that is used for human body and animal body by the medicament of the prepared active compound of the present invention, with prevention, alleviate and/or treat disease.
Can use active compound or its medicament in the mode that local, oral, non-enteron aisle, intraperitoneal and/or rectum use, wherein better, especially best with the intravenously result of use with non-enteron aisle result of use.
In general, per 24 hours, by per kilogram of body weight, with the total amount be the 1-40 milligram, best be that the 2-8 milligram provides active compound, or at random divide the several times administration, then, all help to reach the ideal effect no matter for being applied to human body or animal body.Each administration preferably contains 0.1～4 milligram/kg body weight, and especially best is the active compound that contains 0.2～2 milligram/kg body weight.Yet the above-mentioned dosage that provides can change, and particularly depends on the characteristic and the body weight of treatment target, the character of disease and severity, and the character of preparation, the mode of administration and time or number of times difference dosage also can be variant.Therefore, in some cases, as long as use the active compound that lacks than above-mentioned dosage just can be enough; And in other cases, the usage quantity of active compound then must exceed above-mentioned dosage.Any professional all can be according to the expertise of its grasp, decides the optimal dose and the best dosing mode of specific required active compound.
Embodiment 1
Internal diameter is that 2.6 centimetres, length are that the chromatographic column of 40 centimetres (Pharmacia K 26/40) is being filled weak-type cationite (CM-Sephadex
C25).This weak-type cationite has been 4.7 0.2M sodium acetate buffer equilibration by pH.After chromatographic column is filled, it is washed, reduce to 0.1 milli Siemens/cm (mS/cm) up to electric conductivity with the distilled water that outgases.This moment, the packing height of post was 34 centimetres.The substances that adopts is the pre-acarboses of purifying of 5.2 grams, and it also contains salt and other impurity except moisture.Acarbose is dissolved in about 40 milliliters distilled water,, the pH value is adjusted to 4.7, and solution is mixed with 50 milliliters by adding a spot of hydrochloric acid.Inhibitor content is that 446,550 sucrases suppress unit (SIU), corresponding to the pure anhydrous acarbose of 5.75 grams.Flow velocity with 100 milliliters/hour (18.8 centimetres/hour) is added to above-mentioned substance in the post, under 26 ℃, with distilled water wash and wash-out.Sepn process is shown in accompanying drawing 1a.Main fraction is converged, and yield is 5.87 grams, contain 399,300 sucrases and suppress unit, and be 89% of employed inhibitor.Specific activity is that 72 sucrases suppress unit/milligram dry substance.High pressure lipuid chromatography (HPLC) shows that the content in the acarbose dry substance is 93%.
With 800 milliliters of pH is 4.7 0.2M sodium acetate buffer regeneration chromatographic column, then, with the distilled water of 600 milliliters of degassings damping fluid is washed off.
Embodiment 2～5
Method by example 1 finish all embodiment in the table 1, but chromatographic column telescopic temperature changes in elution process.Elution process is as follows: begin to add solution after 3 hours, the post heating thermostat is opened, according to given temperature, reach predetermined numerical value respectively after 3～12 minutes.Table 1 shows reducing of main fraction volume; Eluting temperature is that 70 ℃ example 5 is shown in accompanying drawing 1b.
Table 1
With weak-type cationite (CM-Sephadex
C25)
The relation of elution volume and temperature when acarbose is carried out chromatographic separation
The main fraction volume of embodiment eluting temperature yield high pressure lipuid chromatography (HPLC)
(℃) content (%) (%) measured of (milliliter) (gram)
1 26 1，163 5.87 89 95
2 40 840 6.25 100 92
3 50 570 6.04 91 90
4 60 460 5.92 86 92
5 70 380 6.62 99 94
Embodiment 6
As the process of example 1, with weak-type cationite (CM-Sephadex
C25) packing (Pharmacia K26/70).This exchanger is 4.3 times balances and washing at pH.Packing height is 47 centimetres.Shown in example 1, adopted same substances promptly to use and be dissolved in 200 ml waters, contained 579,000 sucrases and suppressed unit (SIU) through pre-acarbose of purifying.Flow velocity is 117 milliliters/hour (22 centimetres/hour).Water carries out wash-out.As example 1, the saliniferous fraction at first appears in elutriant, is acarbose then.The end of saliferous fraction and acarbose begin to occur at a distance of 162 milliliters.Post is heated to 45 ℃, can accelerates the elution rate of acarbose.The volume of acarbose fraction is 1048 milliliters, and yield is that 577,000 sucrases suppress unit, is 100% of add-on.
Embodiment 7
As the process of example 6, with weak-type cationite (CM-Sephadex
C25) packing.Exchanger has been 4.9 times at pH, is balanced and washs.Add 200 milliliters and contain the testing liquid that 579,000 sucrases suppress unit, and water wash-out above-mentioned substance.The beginning of saliferous fraction and acarbose fraction is 23 milliliters only apart.The volume of main fraction is 707 milliliters.Temperature is increased to 45 ℃.Yield is that 577,000 sucrases suppress unit, is 100% of add-on.
Embodiment 8
Use CM-Sepharose
Cl 6B speed stream exchanger filling chromatographic column (Pharmacia K 26/40); CM-Sepharose
Cl 6B is by the sodium acetate solution balance of 0.2M, and pH is 4.5, and through water washing.Add 40.5 milliliters and suppress the acarbose solution that activity is the pre-purification of 247,300 sucrases inhibition units (SIU).Flow velocity is 100 milliliters/hour (18.8 centimetres/hour).Distilled water with the degassing carries out wash-out; When acarbose begins wash-out, post is heated to 45 ℃.Distance between salt fraction and the acarbose fraction is 38 milliliters, and the volume of main fraction is 600 milliliters.The yield of acarbose is that 247,000 sucrases suppress unit, 100% of the amount of being to use.The content that records in its dry substance with high pressure lipuid chromatography (HPLC) is 98%.
Embodiment 9
As example 8, with the carboxyme-thylcelluose CM 52 that by 0.2M sodium acetate solution balance is 4.5 to pH
(Whatman) filling chromatographic column, and water washs it.The height of weighting material is 36 centimetres.Add 62 milliliters and suppress the acarbose solution that activity is the pre-purification of 394,000 sucrases inhibition unit, shown in example 8, carry out wash-out.The acarbose fraction is right after the salt fraction.The volume of acarbose is 850 milliliters, and yield is that 322,000 sucrases suppress unit, is 82% of input amount.By high pressure lipuid chromatography (HPLC), the content that records in its dry substance is 90%.
Embodiment 10
As example 8, with the Matrex-Cellufine CM that by 0.2M sodium acetate solution balance is 4.5 to pH
(Amicon) packing.And water washs it.Packing height is 37 centimetres.Adding 62 milliliters, to suppress activity be that 394,000 sucrases suppress the unit acarbose solution of thing of purifying in advance, and carry out wash-out shown in example 8.The acarbose fraction is trailed the salt fraction, and distance is 23 milliliters.The volume of acarbose fraction is 960 milliliters, and yield is that 350,000 sucrases suppress unit, is 89% of add-on.By high pressure lipuid chromatography (HPLC), the content that records in its dry substance is 98%.
Claims (4)
1, a kind of method for preparing acarbose, the acarbose that contains at least 90% to 98% (by weight) after the unwatering of described acarbose product, it is characterized in that with pH be 4.3 to 5.0, concentration is that the acarbose aqueous solution of the pre-purification of 1-20% is added to one and contains in the chromatographic column of weak-type cationite as weighting material by weight, add fashionable temperature for not being higher than room temperature, described exchanger has carboxyl functional group, and with dextran, agarose and Mierocrystalline cellulose are matrix, perhaps this exchanger is derived by the above-mentioned substance that adds polyacrylamide and is obtained, and the distilled water with the degassing carries out wash-out to chromatographic column specially, after salt and colored component wash-out, post is heated to 25-95 ℃ with the wash-out acarbose, and when needed, acarbose is separated from elutriant with usual way.
2, by the described method of claim 1, the volume that it is characterized in that joining the pre-purification acarbose solution of chromatographic column is equivalent to the packing volume of chromatographic column.
3, by the described method of claim 2, the volume that it is characterized in that pre-acarbose solution of purifying is less than 60% of chromatographic column volume.
4, by each described method in the claim 1 to 3, it is characterized in that, in 4 to 25 ℃ temperature range, add pre-acarbose solution of purifying, and after salt and colored component wash-out, post is heated to 40-70 ℃.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853543999 DE3543999A1 (en) | 1985-12-13 | 1985-12-13 | HIGH PURITY ACARBOSE |
| DEP3543999.8 | 1985-12-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86108259A CN86108259A (en) | 1987-07-29 |
| CN1013866B true CN1013866B (en) | 1991-09-11 |
Family
ID=6288309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86108259A Expired CN1013866B (en) | 1985-12-13 | 1986-12-13 | Process for preparation of highly pure acarbose |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4904769A (en) |
| EP (1) | EP0226121B1 (en) |
| JP (2) | JP2502551B2 (en) |
| KR (1) | KR940004065B1 (en) |
| CN (1) | CN1013866B (en) |
| AT (1) | ATE71951T1 (en) |
| BG (1) | BG49497A3 (en) |
| CA (1) | CA1288768C (en) |
| DE (2) | DE3543999A1 (en) |
| DK (1) | DK164870C (en) |
| ES (1) | ES2038591T3 (en) |
| HU (1) | HU196219B (en) |
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|---|---|---|---|---|
| CN1296050C (en) * | 2003-12-10 | 2007-01-24 | 浙江海正药业股份有限公司 | Acarbose enteric coated tablets and its prepn. method |
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|---|---|---|---|---|
| IT1293819B1 (en) * | 1997-08-05 | 1999-03-10 | Univ Massachusetts Lowell | PROCEDURE FOR THE PREPARATION OF ACARBOSE |
| DE19802700A1 (en) * | 1998-01-24 | 1999-07-29 | Bayer Ag | Preparation of fast-dissolving tablets for controlling blood sugar levels |
| EA003101B1 (en) | 1998-03-19 | 2002-12-26 | Бристол-Майерз Сквибб Компани | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
| GEP20033045B (en) | 1998-09-17 | 2003-08-25 | Bristol Myers Squibb Co | Method for Treating Diabetes |
| AU7457300A (en) * | 1999-10-28 | 2001-05-08 | Chong Kun Dang Pharmaceutical Corp. | A process for preparing acarbose with high purity |
| US6586438B2 (en) | 1999-11-03 | 2003-07-01 | Bristol-Myers Squibb Co. | Antidiabetic formulation and method |
| DK1248604T4 (en) | 2000-01-21 | 2012-05-21 | Novartis Ag | Combinations containing dipeptidyl peptidase IV inhibitors and antidiabetic agents |
| US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
| ATE343391T1 (en) * | 2000-05-24 | 2006-11-15 | Pfizer | TREATMENT OF RAMEN ACIDOSE WITH AMYLASE INHIBITORS |
| CA2416767A1 (en) | 2000-08-07 | 2002-02-14 | Ranbaxy Signature Llc | Liquid formulation of metformin |
| WO2002012256A1 (en) * | 2000-08-07 | 2002-02-14 | Biogal Gyogyszergyar Rt | Method for purification of acarbose |
| FI20002148A (en) * | 2000-09-29 | 2002-03-30 | Xyrofin Oy | Method for recovering products |
| FI20002149A (en) * | 2000-09-29 | 2002-03-30 | Xyrofin Oy | Purification of saccharides by chromatographic separation |
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Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2347782C3 (en) * | 1973-09-22 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Amino sugar derivatives, processes for their preparation and medicaments containing these compounds |
| US4062950A (en) * | 1973-09-22 | 1977-12-13 | Bayer Aktiengesellschaft | Amino sugar derivatives |
| DE2719912C3 (en) * | 1977-05-04 | 1979-12-06 | Bayer Ag, 5090 Leverkusen | Process for the isolation of 0- | 4,6-dideoxy-4- [JJl SO, 4,6 / 5) -4,5,6-trihydroxy-3-hydroxymethyl-2cyclohexen-1-yl] -amino] - a - D-glucopyranosyl} - (I right arrow 4) -0- a D-glucopyranosyl- (l right arrow 4) -D-glucopyranose from culture broths |
| US4526784A (en) * | 1981-05-05 | 1985-07-02 | Bayer Aktiengesellschaft | Amino-cyclitol derivatives and medicaments containing them |
| DE3123520A1 (en) * | 1981-06-13 | 1982-12-30 | Bayer Ag, 5090 Leverkusen | SATURED AMINOCYCLITE DERIVATIVES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE3439008A1 (en) * | 1984-10-25 | 1986-04-30 | Bayer Ag, 5090 Leverkusen | POLYMERISATES FOR CLEANING ACARBOSE |
-
1985
- 1985-12-13 DE DE19853543999 patent/DE3543999A1/en not_active Withdrawn
-
1986
- 1986-12-02 EP EP86116773A patent/EP0226121B1/en not_active Expired - Lifetime
- 1986-12-02 AT AT86116773T patent/ATE71951T1/en not_active IP Right Cessation
- 1986-12-02 ES ES198686116773T patent/ES2038591T3/en not_active Expired - Lifetime
- 1986-12-02 DE DE8686116773T patent/DE3683611D1/en not_active Expired - Lifetime
- 1986-12-10 BG BG77451A patent/BG49497A3/en unknown
- 1986-12-10 JP JP61292667A patent/JP2502551B2/en not_active Expired - Lifetime
- 1986-12-11 US US06/940,713 patent/US4904769A/en not_active Expired - Lifetime
- 1986-12-11 CA CA000525014A patent/CA1288768C/en not_active Expired - Lifetime
- 1986-12-12 DK DK598686A patent/DK164870C/en not_active IP Right Cessation
- 1986-12-12 HU HU865203A patent/HU196219B/en unknown
- 1986-12-12 KR KR1019860010629A patent/KR940004065B1/en not_active IP Right Cessation
- 1986-12-13 CN CN86108259A patent/CN1013866B/en not_active Expired
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1996
- 1996-01-29 JP JP8034402A patent/JP2628853B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1296050C (en) * | 2003-12-10 | 2007-01-24 | 浙江海正药业股份有限公司 | Acarbose enteric coated tablets and its prepn. method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN86108259A (en) | 1987-07-29 |
| HUT43083A (en) | 1987-09-28 |
| EP0226121A3 (en) | 1989-03-22 |
| CA1288768C (en) | 1991-09-10 |
| DK598686A (en) | 1987-06-14 |
| DE3543999A1 (en) | 1987-06-19 |
| JPH08245683A (en) | 1996-09-24 |
| JP2502551B2 (en) | 1996-05-29 |
| KR940004065B1 (en) | 1994-05-11 |
| DK164870B (en) | 1992-08-31 |
| ES2038591T3 (en) | 1993-08-01 |
| EP0226121B1 (en) | 1992-01-22 |
| DE3683611D1 (en) | 1992-03-05 |
| ATE71951T1 (en) | 1992-02-15 |
| KR870006074A (en) | 1987-07-09 |
| US4904769A (en) | 1990-02-27 |
| JP2628853B2 (en) | 1997-07-09 |
| DK164870C (en) | 1993-01-11 |
| EP0226121A2 (en) | 1987-06-24 |
| BG49497A3 (en) | 1991-11-15 |
| JPS62155288A (en) | 1987-07-10 |
| HU196219B (en) | 1988-10-28 |
| DK598686D0 (en) | 1986-12-12 |
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